Toxic β-amyloid (Aβ) aggregates are hypothesized to cause Alzheimer’s disease (AD) by driving a neurodegenerative cascade of events that leads to a loss of synapses and neurons, culminating in the characteristic progressive cognitive decline of the disease. Antibody-based immunotherapy to break down existing Aβ aggregates and interrupt the production of new ones has been widely explored but thus far has been unsuccessful in patients. Now, Sevigny et al. report encouraging results from a placebo-controlled trial of aducanumab, a monoclonal antibody that selectively binds to the oligomeric and fibrillar forms of Aβ.

First, the group systemically administered aducanumab to a mouse genetic AD model and observed that it effectively bound parenchymal brain Aβ and reduced both soluble and insoluble forms of Aβ deposits in a dose-dependent manner, possibly through microglial clearance. In the phase 1b trial, 165 patients clinically diagnosed with early or mild AD and harboring positive signs of Aβ by PET scan were treated monthly with 1, 3, 6 or 10 mg kg-1 intravenous infusions of aducanumab or placebo for 1 year. Aducanumab decreased Aβ detectable by PET scan in a dose- and time-dependent manner, an effect not seen in patients treated with placebo. Patients exhibiting the most substantial reduction in brain Aβ also showed slower cognitive decline, offering a preliminary but tantalizing glimpse into the potential for targeting Aβ aggregates to reverse cognitive dysfunction. The main adverse effect of aducanumab was amyloid-related imaging abnormalities indicative of vasogenic edema (an abnormal buildup of fluid in extracellular space originating from blood vessels), which occurred dose-dependently and generally resolved within the first 12 weeks. Further effort to pinpoint a dose that neutralizes aggregates with minimal side effects is now needed.

Importantly, these results are consistent with a causative role for amyloid aggregates in AD progression. Because the study was underpowered for detecting effects on clinical measures, confirmation of findings related to cognitive function will be necessary in subsequent trials with larger patient cohorts. Nevertheless, Sevigny et al. provide compelling evidence that aducanumab reduces brain Aβ in both rodent models and humans and shows substantial promise as a disease-modifying AD treatment.